Genetics. Published Articles Ahead of Print: April 19, 2006, Copyright © 2006
doi:10.1534/genetics.105.054007


A more recent version of this article appeared on May 1, 2006.

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The Dunce cAMP Phosphodiesterase PDE-4 Negatively Regulates G{alpha}s - dependent and G{alpha}s - independent cAMP pools in the C. elegans Synaptic Signaling Network

Nicole K. Charlie 1, Angela M. Thomure 1, Michael A. Schade 1 and Kenneth G. Miller 1*

1 Oklahoma Medical Research Foundation

* To whom correspondence should be addressed. E-mail: millerk{at}omrf.ouhsc.edu.

Submitted on November 28, 2005
Revised on January 13, 2006
Accepted on 13 January 2006


Abstract

Forward genetic screens for mutations that rescue the paralysis of ric-8 (Synembryn) reduction-of-function mutants frequently reveal mutations that cause hyperactivation of one or more components of the G& [alpha]s pathway. Here, we report that one of these mutations strongly reduces the function of the Dunce cAMP phosphodiesterase PDE-4 by disrupting a conserved active site residue. Loss-of-function and neural overexpression of PDE-4 have profound and opposite effects on locomotion rate, but our live animal drug- response assays suggest that loss of PDE-4 function does not affect steady-state acetylcholine release or reception. Our genetic analysis suggests that PDE-4 regulates both G{alpha}s - dependent and G{alpha}s - independent cAMP pools in the neurons controlling locomotion rate. By immunostaining, PDE-4 is strongly expressed throughout the nervous system, where it localizes to small regions at the outside boundaries of synaptic vesicle clusters as well as intersynaptic regions. The synaptic subregions containing PDE-4 are distinct from those containing active zones, as indicated by co-staining with an antibody against the long form of UNC-13. This highly focal subsynaptic localization suggests that PDE-4 may exert its effects by spatially regulating intrasynaptic cAMP pools.

Key Words: C. elegans, Dunce cAMP phosphodiesterase, G{alpha}s, neurotransmitter release, signal transduction




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